Is EHMT2 p.Pro167Arg (c.500C>G) pathogenic?

EHMT2 p.Pro167Arg (c.500C>G) is classified Uncertain significance in EHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0995); Ultra-rare (popmax 0.0117%, amr).

How common is EHMT2 p.Pro167Arg (c.500C>G) in the general population?

EHMT2 p.Pro167Arg (c.500C>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about EHMT2 p.Pro167Arg (c.500C>G)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

EHMT2 p.Pro167Arg

c.500C>G · VCV4017027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP -0.091, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 8,166 bp · p 0.79 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,994 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,612,844 alleles · ultra-rare exomes 6/1,460,778 · genomes 1/152,066 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EHMT2
Protein: p.Pro167Arg
Coding: c.500C>G
MANE Select: NM_006709
Type: single nucleotide variant
Location: chr6:31896345 (GRCh38)
Gene constraint: LOEUF 0.492 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 69.25 · 34 PDB
Residue 167: the 'disordered' region

Full EHMT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EHMT2 p.Ala1077Thr Pathogenic ★★ same type
EHMT2 p.Ala1077Ser Pathogenic ★ same type
EHMT2 p.Asn1112Ser Pathogenic ★ ⚠ same type
EHMT2 p.Lys1162Arg Pathogenic ★ same type
EHMT2 p.Phe1158Leu Pathogenic ★ same type
EHMT2 c.328+2T>G Uncertain significance ★ same type
EHMT2 p.Ala137Ser Uncertain significance ★ ⚠ same type
EHMT2 p.Ala17Pro Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ehmt2-p-pro167arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown